洛匹那韦/利托那韦治疗冠状病毒感染的研究进展

洛匹那韦/利托那韦(LPV/r)是国家卫生健康委员会和国家中医药管理局推荐的新型冠状病毒肺炎(COVID-19)抗病毒治疗药物之一。几项体外试验研究结果显示,LPV/r有抑制SARS病毒和中东呼吸综合征(MERS)冠状病毒的作用,但也有研究并未发现其有抑制SARS病毒的活性或活性较弱。2篇文献报道了LPV/r治疗SARS有一定临床疗效,1篇文献报道了LPV/r治疗1例MERS患者取得成功。近来也有少量LPV/r治疗COVID-19的报道,但是均尚缺乏高质量的对照研究。     

Drug monitoring and viral response to lopinavir/ritonavir or saquinavir/ritonavir containing regimens in individuals infected with the human immunodeficiency virus type 1

The aim of this study was to correlate results of therapeutic drug monitoring, genotypic resistance and viral response to lopinavir/ritonavir (LPV/r) or saquinavir/ritonavir (SQV/r) containing antiretroviral regimens. The retrospective short-term study included 20 patients with LPV/r and 20 patients with SQV/r containing highly active antiretroviral therapy (HAART). At baseline 7 LPV/r patients and 10 SQV/r patients had CD4+T cell counts above 410 cells/microl. After 6 months CD4+T cells had doubled in 5 LPV/r and 2 SQV/r patients. In LPV/r patients the mean serum concentration of lopinavir (LPV) was 2.6 ppm and 67% of all LPV/r samples had 50 or fewer viral copies/ml. In SQV/r patients the mean serum concentration of saquinavir (SQV) was 2.1 ppm. 79% of all SQV/r samples had 50 or fewer viruses/ml. Pharmacoenhanced regimens efficiently suppress human immunodeficiency virus type 1 (HIV-1) and the risk of developing resistance mutations is therefore reduced. The implementation of drug monitoring is an additional tool to determine optimal treatment conditions.     

Monotherapy with lopinavir/ritonavir

Despite the unprecedented pace of development of drugs for the treatment of a viral disease and the unquestionable efficacy of antiretroviral therapy, there is a need for less toxic and cheaper regimens that could simplify the treatment of HIV infection without sacrificing efficacy. The favorable pharmacokinetic profile and the high genetic barrier of boosted protease inhibitors make them ideal candidates for use as monotherapy. Given the encouraging results of available studies on lopinavir/ritonavir monotherapy in patients with no prior failure with protease inhibitors, it may be warranted to conduct trials to investigate the cost-effectiveness of lopinavir/ritonavir monotherapy as second-line therapy in resource-constrained settings where virologic monitoring is not feasible. In addition, larger trials with longer follow up, with particular attention to the potential consequences of viral replication in sites where the penetration of protease inhibitors may be poor, are needed before this strategy can be considered for routine use.     

Pharmacokinetics of lopinavir/ritonavir in HIV/hepatitis C virus-coinfected subjects with hepatic impairment

The effect of hepatic impairment on lopinavir/ritonavir pharmacokinetics was investigated. Twenty-four HIV-1-infected subjects received lopinavir 400 mg/ritonavir 100 mg twice daily prior to and during the study: 6 each with mild or moderate hepatic impairment (and hepatitis C virus coinfected) and 12 with normal hepatic function. Mild and moderate hepatic impairment showed similar effects on lopinavir pharmacokinetics. When the 2 hepatic impairment groups were combined, lopinavir Cmax and AUC12 were increased 20% to 30% compared to the controls. Hepatic impairment increased unbound lopinavir AUC12 by 68% and Cmax by 56%. The effect of hepatic impairment on low-dose ritonavir pharmacokinetics was more pronounced in the moderate impairment group (181% and 221% increase in AUC12 and Cmax, respectively) than in the mild impairment group (39% and 61% increase in AUC12 and Cmax, respectively). While lopinavir/ritonavir dose reduction is not recommended in subjects with mild or moderate hepatic impairment, caution should be exercised in this population.     

Characterization of resistant HIV variants generated by in vitro passage with lopinavir/ritonavir

Lopinavir (LPV, formerly ABT-378) is an HIV protease inhibitor (PI) that is co-administered with a small amount of ritonavir (RTV), which greatly increases and sustains the plasma levels of LPV. Lopinavir/ritonavir (LPV/r) has shown potent antiviral activity in both therapy-nai;ve and PI-experienced patients. To assess the effect of pharmacologically relevant ratios of LPV/RTV (LPV/r) on the emergence of resistant HIV in vitro, HIV-1 pNL4-3 was passaged in the presence of increasing concentrations of LPV alone and LPV/r. Passages with fixed 5/1 and 15/1 concentration ratios of LPV/r initially selected I84V and I50V/M46I mutants, respectively. Selection with LPV alone also generated the same initial mutants (I50V/M46I) as the 15/1 LPV/r passage. Further passage produced other mutations previously found to be associated with PI-resistance. Phenotypic susceptibility to both LPV and RTV decreased with successive passages, irrespective of whether RTV was present in the selection experiment. Furthermore, in the two selection experiments that included RTV (at either 5/1 or 15/1 LPV/r ratio), the IC(50) of RTV at each passage evaluated was at least five-fold higher than the concentration of RTV employed at that passage, while the IC(50) of LPV toward the passaged virus was similar to the concentration of LPV used at that passage, indicating that the selective pressure was attributable to LPV and not RTV.     

Safety of lopinavir/ritonavir for the treatment of HIV-infection

Kaletra, a fixed-dose co-formulation of lopinavir/ritonavir, was the first boosted protease inhibitor developed for the treatment of HIV-infection. In September 2000, the US FDA granted Kaletra fast-track approval as data showed a higher efficacy in the treatment of HIV-infection than standard protease inhibitors of that time. Although potency was of major concern in the early years of highly active antiretroviral therapy (HAART), presently, with the perspective of HIV-infection becoming a chronic but well controllable disease, other issues begin to draw increased attention in the long-term management of HIV-infected patients. Among general health issues such as cardiovascular disease, metabolic disorders or hepatitis co-infection, the long-term toxicity and safety of HAART is an important concern when choosing antiretroviral drugs for each individual patient. In this review, the authors report on the safety of lopinavir/ritonavir in the treatment of HIV-infected patients, and focus on special patient groups and relevant safety issues.     

洛匹那韦/利托那韦在冠状病毒治疗中的应用

目的：近20年来全球多次发生冠状病毒导致的严重危害公众健康的公共卫生事件，其高的传播效率、严重的感染后果以及捉摸不定的流行时间对人类健康构成严重威胁，而针对冠状病毒的治疗目前暂缺乏特效药物。HIV蛋白酶抑制剂复合制剂洛匹那韦/利托那韦广泛用于HIV的治疗，而用于治疗冠状病毒感染则相对少见。本文着重介绍洛匹那韦/利托那韦的药理作用、药动学特点及在冠状病毒感染治疗中的应用。     

Alopecia induced by lopinavir plus ritonavir therapy in an HIV patient

The most commonly reported side effects related to lopinavir/ritonavir are diarrhea, vomiting, headache, nausea, and increased serum triglycerides and cholesterol levels. About 4% of the patients prescribed lopinavir/ritonavir stop taking it because of side effects. Alopecia, generally involving the scalp, has been reported in patients with HIV infection treated with indinavir but not with lopinavir/ritonavir. We present a 62-year-old man with HIV infection, stage B2, who experienced alopecia totalis of his scalp, eyebrows, and eyelashes beginning 18 months after initiating antiretroviral treatment including lopinavir/ritonavir. No hair loss on the arms, legs, and pubic area was observed. Our patient's drug regimen consisted of lopinavir/ritonavir, efavirenz, and stavudine; in addition, the patient was receiving treatment for diabetes with glivenclamide and metformin for the last 3 years. These drugs have not been shown to cause alopecia. Alopecia reversed completely 2 months after substituting nelfinavir for lopinavir/ritonavir without any other change of treatment and his eyelashes and eyebrows grew back as well. To our knowledge, this is the second case of lopinavir/ritonavir-associated alopecia totalis reported in the international literature.     

洛匹那韦/利托那韦片致迟发性过敏性休克

1位29岁女性护士在治疗新型冠状病毒感染患者期间不慎被患者用过的针头扎破手指。因担心职业暴露感染口服洛匹那韦/利托那韦片(洛匹那韦200 mg/利托那韦50 mg)2片,2次/d。首次服药4 h后出现全身红色皮疹,伴颜面部肿胀。给予氯苯那敏片8 mg口服,地塞米松磷酸钠注射液5 mg肌内注射。服药后8.5 h患者出现大汗淋漓,面色苍白,伴腹痛、腹泻,血压70/50 mmHg(1 mmHg=0.133 kPa),体温35.2℃,心率87次/min,呼吸22次/min,脉搏微弱,四肢发冷,血氧饱和度0.93。诊断为洛匹那韦/利托那韦致过敏性休克,给予静脉扩容、鼻导管吸氧及心电监护。患者症状逐渐缓解,2.5 h后患者血压恢复至108/89 mmHg,次日皮疹消退。     

Time-dependent interaction between lopinavir/ritonavir and fexofenadine

This study investigated the effect of single-dose and steady-state lopinavir/ritonavir on the exposure to fexofenadine, as a measure of P-glycoprotein activity. Sixteen volunteers (8 women) received single-dose oral fexofenadine 120 mg alone, in combination with single-dose ritonavir 100 mg or lopinavir/ritonavir 400/100 mg (randomized 1:1, stratified by sex), and in combination with steady-state lopinavir/ritonavir 400/100 mg twice daily. Single-dose ritonavir and lopinavir/ritonavir increased the area under the fexofenadine plasma concentration-time curve from 0 to infinity (AUC(infinity)) by 2.2- and 4.0-fold, respectively (P < .02). Steady-state lopinavir/ritonavir increased the fexofenadine AUC(infinity) by 2.9-fold. No changes were observed in the fexofenadine elimination half-life (P > .12). The fexofenadine AUC(infinity) was increased by lopinavir/ritonavir, likely due to increased bioavailability secondary to P-glycoprotein inhibition. After repeated administration of lopinavir/ritonavir, the interaction was attenuated compared to the single-dose effect, although a net inhibitory effect was maintained. Time-dependent inhibition of P-glycoprotein by lopinavir/ritonavir should be considered when P-glycoprotein substrates are coadministered.     

洛匹那韦/利托那韦临床应用概述

洛匹那韦/利托那韦是复方制剂,洛匹那韦与病毒蛋白酶催化部位结合干扰病毒装配过程,低剂量利托那韦抑制人体CYP3A介导洛匹那韦代谢,提高生物利用度,提高血浆中洛匹那韦药物浓度。本文对洛匹那韦/利托那韦在病毒感染性疾病的临床应用、不良反应、药物相互作用等进行介绍。     

依非韦伦、奈韦拉平或洛匹那韦/利托那韦方案对艾滋病病毒/艾滋病病人血脂代谢的长期影响

目的 观察依非韦伦（EFV）、奈韦拉平（NVP）或洛匹那韦/利托那韦（LPV/r）方案对艾滋病病毒（HIV）感染者/艾滋病（AIDS）病人（简称HIV/AIDS病人）血脂代谢的长期影响。方法 采用回顾性队列研究的方法,以南京市第二医院2013年3月至2018年12月启动抗逆转录病毒治疗（ART）的成年HIV/AIDS病人为研究对象,收集其人口学、临床基线和治疗随访数据,分析纳入对象在随访期间三酰甘油（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、空腹血糖（FPG）以及TC/HDL-C的检测水平及异常率的变化情况。结果 与EFV相比,NVP组在具体随访期间有较高TG异常率和较低的HDL-C、FPG和TC/HDL-C异常率,两组总的血脂异常率随时间增加有明显变化;相较EFV,LPV/r组在具体随访期间有较低的FPG异常率和较高的TG、TC以及TC/HDL-C异常率,两组异常TG、TC、HDL-C、FPG和TC/HDL-C百分率随时间增加有明显变化。结论 与EFV相比,NVP可能与有利的脂质谱相关但LPV/r可能对血脂危害更大,另外,EFV对血...     

LC-MS/MS for immunosuppressant therapeutic drug monitoring

Due to their narrow therapeutic indices and highly variable pharmacokinetics, therapeutic drug monitoring is necessary to individualize immunosuppressant dosage following organ transplantation. Until recently, monitoring was performed primarily using immunoassays, however, there is an increasing shift to HPLC coupled with MS/MS, due to its greater sensitivity and specificity. Online sample clean-up with either a single analytical column or with 2D chromatography significantly reduces manual handling and is essential to minimize matrix effects and maximize specificity and, coupled with rapid chromatography, allows the simultaneous analysis of the major immunosuppressants, with rapid sample throughput. Thus, LC-MS/MS is an attractive and versatile technique that facilitates rapid development of analytical methods, including new immunosuppressants as they become approved for clinical use.     

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

Purpose  

This study aimed to investigate the effect of antivirals ritonavir and lopinavir/ritonavir on the pharmacokinetics and pharmacodynamics of oral oxycodone, a widely used opioid receptor agonist used in the treatment of moderate to severe pain.     

Evidence for time-dependent interactions between ritonavir and lopinavir/ritonavir plasma levels following P-glycoprotein inhibition in Sprague-Dawley rats

The interaction between verapamil, a P-glycoprotein (P-gp) inhibitor, with ritonavir and lopinavir/ritonavir (LPV/r) after acute and chronic treatment was investigated in rats. Rats were divided into 4 groups, viz. Group 1: ritonavir, 20 mg/kg/d (n=18), group 2: ritonavir, 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18), group 3: LPV/r, 80 and 20 mg/kg/d (n=17) and group 4: LPV/r, 80 and 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18). Blood samples were collected after decapitation on days 1, 7 and 21. Lopinavir and ritonavir plasma levels were simultaneous determined by a validated LC/MS/MS method. The lower limit of quantification for both ritonavir and lopinavir was 0.078 μg/ml. Verapamil significantly increased ritonavir plasma levels, administered as monotherapy, following acute (p<0.005) and chronic treatment (day 21) (p<0.005). During acute (but not chronic) LPV/r treatment, verapamil also increased the lopinavir levels (p<0.05). A time or exposure dependent pharmacokinetic interaction was thus observed between verapamil and ritonavir whether administered alone or after the lopinavir-ritonavir combination (LPV/r). This interaction occurred most prominently after acute treatment, and became less pronounced over time. This study indicates the importance of a longer time frame to investigate enzyme based drug interactions in rat models.